Art of preparing xanthin derivatives.



Il'o. $57329.

Patented April 12,1904

PATENT OFFICE.

MITFORD o; MASSIE, or wAsHmGroN, DISTRICT or COLUMBIA, ADMIN- ISTRATOR or FRITZ non, DECEASED, ASSIGNOR To 0. r. BOEHRINGER & SOEHNE, or MANNHEIM-WALDHOF,"GERMANY, A FIRM.

ARTIOF PREPARING XANTHIN DERIVATIVES.

SPECIFICATION forming part of Letters Patent N0. 757,328, dated April 12, 1904:.

Application filed February 7,1903.

duly-constituted administrator of the estate:v

of said FRITZ AoH, deceased, do hereby declare the following to be a full, clear, and ex-,

act description of the said invention of said decedent, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relates to the art of I 5 preparing derivatives of alkylized xanthins,

or, more specifically, the manufacture of haloid substitution products of alkylized xanthins or of xanthin homologues.

The object of this invention is to obtain a new series of compounds which may be employed for the production of pharmacal preparations or bodies.

In United States Patent No. 667,381, dated February 5, 1901, and German Patent No.

been described a number of homologues of xanthin in which a methyl group is bound to the carbon atom occupying the position 8. It was found in the course of the inventors 3 experiments with these bodies that the hydrogen atoms of this methyl group may be readily replaced by a haloid element, particularly chlorin. It was found inthis connection that according as the proportions of the reagents are chosen so that one, two, or three molecules of chlorin are caused to act on a molecule of an 8-methyl-xanthin, mono, di, or tri chloro substitution products, respectively, of the named 8-methyl xanthins are obtained. 4 Thus, for example, an 1-3-7-trimethyl-8-monochloro-methyl-xanthin, having the structural formula:

CH3. N GO $erial No. 142,589. (Specimens) ixanthin or 8methyl-caffein by causing a mole- .cule of chlorin to act on a molecule of this body. If two molecules of chlorin are caused to act on one molecule of 87-methyl-caffein, two of the hydrogen atoms of the 8-methyl group 7 are replaced, giving riseto 1-3-7-8-trymethyl- 8 dichloromethyl xanthin or 8 dichloromethyl-caffein, and, finally, if the proportions of the chlorin to the said starting compound are as three to one, a compound, which are designated as 8-trichloromethylcaffein, having the formula: I

results. The reaction proceeds in a similar manner, resulting ina chloro substitution product if chlorin is caused to react on 3-7-8 trimethyl-xanthin or 8-methyltheobromin and in general on the alkylized xanthins above defined. 25 128,212, issued February 8, 1902, there have This invention may be carried out in the simplest manner by causing chlorin gas in the properly-calculated amounts to act upon an 8 methyl xanthin derivative (under which term are of course included the salts, such as the chloride of these bodies) in solution or suspension. It is to be understood, however, that other chloridizing agentssuch, for example, as sulfurylchlorid or sulfuric oxychlorid (SO2Cl2)may be successfully employed and are included within the scope of the invention and claims.

The new compounds obtained under this invention are well-defined tolerably-stable bodies, differing from the starting compounds in possessing no basic properties, and the trichloro methyl xanthins comprised among them are obtained as colorless crystalline solids, which melt at higher temperatures, are not volatile at ordinary atmospheric pressure, and are soluble in hot chloroform. They are all to beus'ed in the arts as starting materials tin he manufacture of pharmacal products.

A number of examples embodying what is considered the preferred manner of carrying the invention into effect will now be recited in detail.

Example 1-Prepamti0n of 8-.Zl1bn0chl07'0- metkyZ-cafein.

of chloroform free from water are added, and the whole is then heated to boiling in a reflux apparatus andmaintained at this temperature,

chlorin gas being. concurrently introduced.

After about eighteen grams of chlorin, corresponding to about one molecule, have been consumed solution will have taken'place. The reaction proceeds according to the equation:

The chloroform is then recovered from the solution by distilling off, which leaves a thick syrupy residue, which on cooling solidifies into a crystalline mass. The chloro' compound thus obtained is purified by redissolving in alcohol or, preferably, in acetic ether, from which solution it crystallizes in the form of snow-white coarse needles.

By analysis the formula of the new compound is found to be:

CHaN-CO l l on. C9H11O2N4Cl= OG C-N I II G.CH2Cl V CH3.NC-N This new compound melts between 208 and 210 centigrade.

readily soluble in boiling alcohol.

Two hundred grams of dry S-methyl-cafl'ein are dissolved in five hundred cubic centime-- ters of chloroform free from water, and intothis solution at ordinary room temperatureone'hundred and forty grams of chlorin, corresponding to about two molecules, are introduced while constantly stirring or agitating. the solution, a small increase of temperature occurring during'this treatment.

This

by the acetic ether. according to the equation:

It is readily soluble in hot chloroform and in hot acetic ether, but not so f The chloroform is thereupon recovered to the fullest extent possible by distilling oif, and the crystalline residue is finely comminuted or powdered and boiled with about five times its weight of acetic ether in a reflux apparatus. As a result of this treatment almost pure 8-dichloromethyl-caflein is left as a residue, the

mono-chloro compound which was mixed with it as an impurity having been dissolved out The reaction proceeds CH3. N- ('30 CHaN-CO OC C--N. CH3

' 8-dichloromethyl-caifein is readily soluble in chloroform, but more difficultly soluble in alcohol, from which it crystallizes in colorless 1 needles, having a melting-point at about 230 to 232 centigrade. its formula is:

According to analysis CH8-N CO l coHmNiozclz oo c-Ncrn Example 3-Preparatz'0n 0f 8 Tm'chloromet/LyZ-cafein. (a) By means of chlorin gas.Fifty-five grams of chlorin gas, corresponding to about three molecules, are introduced at a temperature of about 20 centigrade into a solution of fifty grams of dry S-methyl-caffein in two hundred and fifty cubic centimeters of chloroform free from water, the said solution being constantly stirred during the introduction of the gas.

The solution is then evaporated to dryness, whereby the trichloro compound is left as a residue. The reaction proceeds according to the equation:

ccH I N 3 The residue is then purified by dissolving in acetic ether and crystallizing therefrom. The

lcH..N c N lution.

new cbm ound is obtained in' white. needles. having a melting-point of about 182 to 184 'centigrade. Its formula is ascertained to be:

()Habfl- SJO cataract: o c ON.CH3

with ice and which is also constantly kept in .motion while the'sulfuryl-chlorid is introduced. After all of the sulfuryl-chlorid has been run in and the evolution of hydrochloric- A acid has ceased the chloroform is distilled off.

The residual crude. product, the 8-trichloromethylcaffein, is purified in the manner described above. The reaction by which the new 1 body is formed is expressed .by theequation:

- I l v I C-N. GHa+3SO2Cl2 (lOH3 Example 4Preparatim of 8- Tm'cklorovnctipyZ-t/teobromivi.

One hundredgrams of 8-niethyl-theobromin are suspended in two thousand cubic centime ters of phosphorus oxychlorid in which are dis-' solved one hundred and thirty grams of chlorin. This mixture is then constantly shaken or agitated for four hours at ordinary temperature. The chlorin is thereby caused to gradually disappear by combining with the theobromin derivative, and the greater portion of the suspended matter gradually goes into so- The whole is thereupon placed on the filter toseparate the small amount of unchanged methyl-theobromin, and'the filtrate Y is thereupon subjected to evaporation in mono sufficient to drive off the phosphorus oxychlorid and to leave the new resultant body, the

8-trichloro methyl-theobromin, or 3-7 -dime v thyl-S-trichloro methyl-Xanthin, as a residue,

which is purified by dissolving in acetic ether and crystallizing therefrom. The crystals 3 thus obtained are in the form of shining prisms,

which contain acetic ether of crystallization, said acetic ether being, however, readily and gradually dissipated when drying the crystals This p ndisnot volatile at ordinary in the air. a This new xanthin derivative melts at about 211 to 212 centigrade.

The formation of the new body is indicated in the equation:

HN- CO I l 00 GN.CH3+3O12:

(lCH3 m wco oc o-norn occls+snci cHaN-b-N This new compound is also distinguished by its non-basic properties by not being volatile at ordinary pressures and being soluble in hot chloroform and by the fact that it forms incolorless crystals.

By proceeding in the manner thus far described one is enabled to obtain mono, di, and tri chloro substitution products of 8-alkyl-xanthins. The invention is broader than this,

however, since it is possible under the same to prepare tetra-chloro substitution products by substituting a Cl atom for one of the hydrogen atoms in a methyl group bound to one 'of the nitrogensin the S-alkyl-xanthin. is effected by submitting the alkyl-xanthin in question to a vigorous chlorinizing action.

Thus, for example, the inventor has succeeded in preparing tetra-chloromethyl-cafifein or 8- trichloromethyl-7-mono chlorom ethyl-1, 3- dimethyl-xanthin having the structural for- OH3.1|\ICO 0o (fi-ngmci cool cum C,N// 3 mula:

'by the following preferred method: A solution of one part, by weight, of 8-methyl-caffein in about eight parts, by weight, of nitrobenzol is heated on a water-bath, and into the so-heated solution-a large excess of chlorin gas is introduced until no more of the same is absorbed. Thereupon the uncomblned chlorin which remams dissolved in the nitro-benzol is expelled as far as possible by introducing into orpassing over the liquid a current of air,

whereupon the greater portion of the nitrobenzol is distilled off from the whole in a vacuum. The residue is then allowed to cool,

whereupon the new compound, the S-trichloromethyl 7 chloromethyl 1, 3 dimethyl xanthin, is thrown out in the form of coarse crystals which are-in a fairly-pure condition without further treatment. For more complete This purification they are redissolved in hot alcohol, from which they separate in the form of large colorless prismatic crystals which melt at about 204 to 205 centigrade. The new compound is soluble in chloroform, difiicu'ltly soluble in alcohol and acetic ether. This new com pound is to serve as a starting material for the manufacture of pharmacal compounds and preparations.

From the above examples it will be noted that the chlorinizing reagent acts on the S-al kyl-Xanthins recited either in solution or in suspension, both of which conditions are here in designated by the comprehensive term bath of 8-alkyl-xanthin or bath of 8- methyl-xanthin in the generic claims. It will also be observed that the resultant compound may have the alkyl group in the posi-' tion 8 chlorinized by replacing two or three of the hydrogen atoms in said alkyl group,

What is claimed, and desired to be secured by Letters Patent, is I 1. In the art of preparing xanthin derivatives, the process which consists in acting upon an S-alkyl-xanthin with an agent which will give up a haloid element.

2. In the art of preparing xanthin derivatives, the process which consists in acting on an 8-alkyl-xanthin with a chlorinizing agent.

3. In the art of preparing xanthin derivatives, the process which consists in acting upon an 8-methyl-xanthin with a chlorinizing agent.

4. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing agent to act on a bath of an 8-alky'l-xanthin.

5. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a solution of an 8-alkyl-xahthin.

6. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a bath of an 8-alkyl-xanthin, the relative proportions being molecular according to the number of chlorin atoms to be bound in the resultant compound.

7 In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a solution of 8-alkyl-xanthin, the relative proportions being molecular according to the number of chlorin atoms to be bound in the resultant compound.

8. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing agent to act on a bath of an S-methyl-xanthin.

9. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a solution of an 8methyl-Xanthin.

10. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a bath of an S-methyl-xanthin, the relative proportions be-' ing molecular according to the number of chlorin atoms to be bound in the resultant compound.

11. In the art of preparing xanthin derivatives, the process which consists in causing a chlorinizing reagent to act on a solution of S-methyl-xanthin, the relative proportions being molecular according to the number of chlorin atoms to be bound in the resultant compound.

, 12. In the art of preparing xanthin derivatives, the process which consists in causing chlorin to act on a bath of an 8-methyl-xanthin.

13. In the art of preparing xanthin derivatives, the process which consists in causing chlorin to act on a solution of an 8-methylxanthin.

14. In the art of preparing xanthin derivatives, the process which consists in causing chlorin to act on a bath of an 8-methyl-xanthin, the relative proportions being molecular according to the number of chlorin-atoms to be bound in the resultant compound.

15. In the art of preparing xanthin derivatives, the process which consists in causing chlorin to act on a solution of an 8-methylxanthin, the relative proportions being molecular according to the number of chlorin atoms to be bound in the resultant compound.

16. The process which consists in acting upon a bath of an 8-alkyl-X'anthin in chloroform with a chlorinizing reagent.

17 The process which consists in acting on a solution of an S-methyI-Xanthin in chloroform with a chlorinizing reagent.

18. The process which consists in acting upon a bath of an 8-alkyl-xanthin in chloroform with chlorin.

19. The process which consists in acting on a solution of an S-methyl-xanthin in chloroform with chlorin.

20. The process which consists in acting on a bath of an 8alkylxanthin in chloroform with a chlorinizing reagent and then, after the reaction is complete, driving oif the chloroform and evaporating to dryness.

21. The process which consists in acting on a bath of an alkylized S-aIkyI-Xanthin in chloroform with a chlorinizing reagent, then after .the reaction is complete, driving off the chloroform and evaporating to dryness.

22. The process which consists in acting on a bath of an 8-methyl-caifein in chloroform with a chlorinizing reagent, then after the reaction is complete, driving off the chloroform and evaporating to dryness.

23. The process which consists in acting on a bath of an 8-methyl-cafiein in chloroform with a chlorinizing-reagent, then after the reaction is complete, driving 'ofl the chloroform and evaporating to dryness, then redissolving in acetic ether and crystallizing therefrom.

24. The process which consists in acting on a bath of an 8-alkyl-xanthin in chloroform with chlorin, then after the reaction is complete, driving off the chloroform and evaporating to dryness.

25. The process which consists in acting on a bath of an alkylized 8-alkyl-Xanthin in chloroform with chlorin, then after the reaction is complete, driving off the chloroform and evaporating to dryness.

26. The process which consists in acting on a bath of an S-methyl-cafiein in chloroform with chlorin, then after the reaction is complete, driving off the chloroform and evaporating to dryness.

27. The process which consists in acting on a bath of an S-methyI-cafiein in chloroform with chlorin, then after the reaction is complete, driving off the chloroform and evaporating to dryness, then redissolving in acetic ether and crystallizing therefrom.

28. As a new chemical'compound, an 8-ch1oro alkyl-xanthin which is distinguished by having the alkyl group in the position 8 chlorinized, and which has substantially no basic properties.

29. As a new chemical compound, an 8-triohloro-alkyl-Xanthin which is distinguished by having the three of the hydrogen atoms in the position 8 replaced by chlorin, and which has substantially no basic properties.

30. As a new chemical compound, an 8-trichloro-methyl-xanthin having the three hydrogen atoms of the methyl group in the position 8 replaced by chlorin, which has substantially no basic properties, and which is distinguished by forming in colorless crystals which melt at a high temperature, which are not soluble in hot chloroform.

31. As a new chemical compound, 8 trichloro-alkyl-caffein, being derived from 8-alkyl-caffein by the substitution of chlorin for three hydrogen atoms in the alkyl group at the position 8, and which has substantially no basic properties.

32. As a new chemical compound, 8-trichloro-methyl-caifein having the formula hereinbefore given, which has substantially no basic properties, which is soluble in acetic ether and hot chloroform and crystallizes'therefrom in White needles having amelting-point of about 182 to 184: centigrade and being stable or non-volatile at ordinary pressures.

In testimony whereof I affix my signature in presence of two witnesses.

MITFORD C. MASSIE, Admm't'stmtor 0 f the estate of Fritz Ac/t, de-

ceased.

Witnesses:

ALBANUs S. T. J OHNSON, L. E. A. OKEEFFE. 

